1. Technical Field
The present invention is generally directed to compounds useful for the preparation of diarylpropanes and methods related to the same.
2. Description of the Related Art
There is great demand for products able to inhibit or prevent excessive pigmentation of the skin. Melanin, the skin's natural pigment, is a nitrogenous polymer synthesized in melanosomes, which are membrane-bound organelle present within melanocytes. Melanin is produced in varying concentrations, depending on skin type (genetic disposition) and environmental conditions. Melanocytes are cells that occur in the basal membrane of the epidermis, and account for between 5% and 10% of the cellular content (approximately 1200-1500 melanocytes/cm2). When stimulated, by factors such as ultraviolet (UV) light, melanocytes divide more rapidly and produce greater quantities of melanin. The melanin is then transported in mature melanosomes to keratinocytes within the epidermis where it becomes visible as a brown skin color.
The over production of melanin can cause different types of abnormal skin color, hair color and other diseases and conditions of the skin. There are primarily two conditions related to skin pigmentation disorders. A darkening of the skin that includes abnormal elevated melanin caused by UV exposure and aging; and abnormal distribution of skin pigments resulting in age spots, liver spots, and drug and wound/disease induced hyperpigmentation (Seiberg et al. (2000) J. Invest. Dermatol. 115:162; Paine et al. (2001) J. Invest. Dermatol. 116:587).
Diarylalkanes are a rare class of natural product which have shown potential for decreasing melanin production and are being investigated for use as skin lightening therapeutics (see e.g., U.S. Pub. No. 2005/0267047). Although more than 179,000 natural compounds are listed in the Dictionary of Natural Products (Chapman & Hall/CRC, Version 12:2 Jan. 2004, available on CD-ROM), only 82 are diarylpropanes. Diarylpropanes have been isolated from a number of different natural sources; however, the low abundance of diarylpropanes of interest in natural sources often necessitates their preparation in the laboratory.
One approach for preparing diarylpropanes has been to completely reduce the corresponding chalcone to the diarylpropane in one step (see e.g., U.S. Pat. No. 5,880,314; J. Chem. Soc. Perkin Trans. 1 (1979), (7), 1661-4; and Lett. In Org. Chem. 2006, 3, 39-41. However, such methods are not robust and are unsuitable for large-scale preparation of diarylpropanes. For example, published methods generally suffer from low yields, poor reproducibility and result in mixtures of compounds which are difficult to separate. Methods and/or compounds to successfully address these, and other, difficulties associated with preparation of diarylpropanes have yet to be suggested.
While significant advances have been made in this field, there remains a need for improved methods for preparation of diarylpropanes as well as compounds useful for the same. In particular, methods and compounds suitable for large-scale preparation of diarylpropanes in high purity are needed. The present invention fulfills these needs, and provides other related advantages.